Cytochrome P450 3A4-mediated interaction of diclofenac and quinidine

Citation
Js. Ngui et al., Cytochrome P450 3A4-mediated interaction of diclofenac and quinidine, DRUG META D, 28(9), 2000, pp. 1043-1050
Citations number
32
Categorie Soggetti
Pharmacology & Toxicology
Journal title
DRUG METABOLISM AND DISPOSITION
ISSN journal
00909556 → ACNP
Volume
28
Issue
9
Year of publication
2000
Pages
1043 - 1050
Database
ISI
SICI code
0090-9556(200009)28:9<1043:CP3IOD>2.0.ZU;2-T
Abstract
The metabolism of diclofenac to its 5-hydroxylated derivative in humans is catalyzed by cytochrome P450 (CYP)3A4. We report herein that in vitro this biotransformation pathway is stimulated by quinidine. When diclofenac was i ncubated with human liver microsomes in the presence of quinidine, the form ation of 5-hydroxydiclofenac increased similar to 6-fold relative to contro ls. Similar phenomena were observed with diastereoisomers of quinidine, inc luding quinine and the threo epimers, which produced an enhancement in the formation of 5-hydroxydiclofenac in the order of 6- to 9-fold. This stimula tion of diclofenac metabolism was diminished when human liver microsomes we re pretreated with a monoclonal inhibitory antibody against CYP3A4. In cont rast, neither cytochrome b(5) nor CYP oxidoreductase appeared to mediate th e stimulation of diclofenac metabolism by quinidine, suggesting that the ef fect of quinidine is mediated through CYP3A4 protein. Further kinetic analy ses indicated that V-max values for the conversion of diclofenac to its 5-h ydroxy derivative increased 4.5-fold from 13.2 to 57.6 nmol/min/nmol of CYP with little change in K-m (71-56 mu M) over a quinidine concentration rang e of 0 to 30 mu M. Conversely, the metabolism of quinidine was not affected by the presence of diclofenac; the K-m value estimated for the formation o f 3-hydroxyquinidine was similar to 1.5 mu M, similar to the quinidine conc entration required to produce 50% of the maximum stimulatory effect on dicl ofenac metabolism. It appears that the enhancement of diclofenac metabolism does not interfere with quinidine's access to the ferriheme-oxygen complex , implicating the presence of both compounds in the active site of CYP3A4 a t the same time. Finally, a similar to 4-fold increase in 5-hydroxydiclofen ac formation was observed in human hepatocyte suspensions containing diclof enac and quinidine, demonstrating that this type of drug-drug interaction o ccurs in intact cells.